Adjuvant treatment for biliary tract tumors: lost in a maze?
Authors: Angela Lamarca, Julien Edeline
Journal: Hepatology (2023)

Single-agent capecitabine was established as the standard adjuvant treatment for biliary tract cancers (BTC) based on the BILCAP study.1–4 Two clinical trials exploring gemcitabine-based chemotherapy5 (either gemcitabine alone in the BCAT study6 or gemcitabine and oxaliplatin in the PRODIGE-12 study7) showed no significant activity. The only recent positive adjuvant clinical trial was the ASCOT study, a randomized phase III study in the Asian population that confirmed the activity of single-agent fluoropyrimidine-based therapy (S-1) in this setting.8 Despite the urgent need, it has become challenging to improve adjuvant strategies for BTC.9 Therefore, the results of studies exploring alternative adjuvant treatment such as cisplatin and gemcitabine (CisGem) in the STAMP10 and ACTICCA-1 (NCT02170090; results awaited) trials are eagerly awaited. The STAMP clinical trial represents an important step in the development of adjuvant strategies for BTC.10 This investigator-led, randomized phase II clinical trial recruited a total of 101 patients over a period of 3.5 years in South Korea and explored the role of adjuvant CisGem (experimental arm) over capecitabine (control arm) in patients with resected extrahepatic cholangiocarcinoma (eCCA) at high risk of recurrence. Unfortunately, the study did not show an improved outcome with CisGem; thus, capecitabine remains the current standard of care in this setting. Despite these negative results, the design and the delivery of this study are, on their own, reasons for which to congratulate the investigators and highlight the very interesting topics for discussion. The trial focused on a specific group of patients with BTC: patients diagnosed with eCCA [both hilar (hCCA) and distal (dCCA)], who had undergone curative surgery with R0 or R1 resection, and who had lymph node positive disease in the surgical specimen. Most of these are known factors for higher risk of recurrence, thus enriching the study for patients with high risk of recurrence. Interestingly, patients with Ca 19.9 ≥100 IU/mL were excluded, which could somehow help identify patients with better outcome within this “high-risk” population selected. Within the 101 patients recruited, 44.6% were hCCA and 55.4% were dCCA, with an R1 margin status in 31.7% of patients. Baseline characteristics were well balanced between the study arms. Patients started treatment within 7 weeks from surgery in both study arms, which may feel short, taking into account the time that patients usually need to recover from surgery in standard clinical practice and also experience from prior studies (ie, 10 weeks from time of surgery to randomization in the BILCAP trial1). Unfortunately, the study did not show any benefit in favor of CisGem either in disease-free survival (DFS) [HR, 0.96 (1-sided 90% CI, 0.71–1.3); p-value=0.430] or overall survival (OS) [HR, 1.08 (1-sided 90% CI, 0.71-1.64); p-value=0.404] in the intention to treat population, with very similar findings in the per-protocol population. It is also worth noting that data were mature (with >70% of events for DFS in both arms) at the time of analysis, thus further follow-up is unlikely to change these findings. In terms of the study design, patients were 1:1 randomized to each arm. Selected stratification factors (primary site and resection margin status) seem appropriate and should probably be adopted in future studies also.9 We are now aware that BTC represents a heterogeneous group of malignancies, with different surgical strategies, biology, and natural history. The fact that the authors chose to focus on 1 subgroup of BTC (eCCA) rather than recruiting all BTC patients is worth mentioning, as this represents an ongoing topic of discussion for the design of future trials in this setting. Within the BILCAP trial, the hCCA derived the least benefit from capecitabine, thus highlighting the importance of this issue.2 While performing BTC-subgroup-specific trials provides a more homogeneous population, the main caveat comes in the form of challenges at the time of recruitment. The open-label design was also appropriate taking into account the way of administration of the treatment options being explored. The fact that it took 3½ years to recruit these 101 patients reflects the challenge of delivering adjuvant studies in BTC, especially when being performed in one single country. To have a feasible and deliverable estimated sample size, unrealistic HRs are often assumed at the time of sample size calculation.7 The STAMP trial was powered to identify an HR of 0.6 (equivalent to an 18% increase in DFS rate at 2 years between arms, estimated 40% with CisGem and 22% with capecitabine) in DFS with a power of 80% and a 1-sided type I error of 10%. This HR might be seen as quite optimistic, given the achieved HR of 0.81 by capecitabine versus observation in the BILCAP trial.2 In addition, studies (STAMP being an example) are sometimes designed taking into account the 1-sided (rather than 2-sided) type I error,8 to bring down the sample size estimation. Aiming for a deliverable sample size, these strategies at the time of study design are, on many occasions, the reason why studies in this setting have been somehow “underpowered,”9 something to be avoided in the future and likely to be overcome by joint efforts and international collaborations. Despite the potential above-mentioned pitfalls identified in the sample size calculation, these may not be the explanation for the negative results in this occasion. The fact that there is no trend in favor of the experimental arm at all, points in the direction of a real lack of activity of CisGem in the adjuvant setting, not just an “underpowered” trial. How can we make sense of this, with CisGem being the standard backbone chemotherapy11,12 in the first-line palliative setting? How did we get into this maze and how can we find the exit? One could wonder whether the absence of benefit from adjuvant CisGem could be due to how this impacts the treatment given at the time of recurrence in the first-line palliative setting. In the STAMP trial, 81% of the patients with recurrence in the CisGem arm received systemic chemotherapy (43% CisGem-, 47% 5-fluorouracil-, and platinum-based combinations). In the capecitabine arm, a similar proportion received systemic treatment (90%), but all received this in the form of CisGem-based schedules (100%). Whether this could impact OS findings could be hypothesized and has been suggested for GEMOX in the PRODIGE-12 trial7; it would not, however, change the DFS outcome data. Patterns of recurrence are of interest, especially when looking into the future and when planning new studies. In the STAMP trial, the pattern of recurrence was predominantly systemic (59% distant recurrence only, 17% combination of both distant and local recurrence). This clearly supports the use of systemic therapy-based approaches for future studies. Recent guidelines are now incorporating recommendations for presurgical 18F-18 fluoro-2-deoxyglucose positron emission tomography to identify occult metastases before surgery and maybe future studies should take this into account for adequate patient selection for surgical and adjuvant studies.3,13 Interestingly, recurrence was local only on 24% of occasions. For patients with local recurrence, radiotherapy-based strategies were utilized in 8% (CisGem arm) and 5% (capecitabine arm) of patients. To reduce the risk of local recurrence, whether consolidation radiotherapy should be incorporated at the time of completion of the systemic adjuvant treatment should be further explored in clinical trials. To do so, identifying the patients at higher risk of local recurrence would be of much relevance, so these could be recruited into such trials. One of the pitfalls of this study that we could highlight is that some of the patients with R1 resection did actually receive additional adjuvant radiotherapy after completion of CisGem or capecitabine (in the absence of recurrence, thus before the primary endpoint-associated event was reached). Authors report that once the adjuvant treatment was completed, 3 of the 16 patients with R1 resection in the CisGem and 5 of the 16 patients with R1 in the capecitabine arm were treated with radiotherapy. Even though numbers are small, this could impact the interpretation of findings and the administration of additional treatments outside the research question should be avoided in future studies, with specific trials to assess the impact of radiotherapy being designed. Albeit cross-trial comparisons are always at risk, 2-year DFS in the adjuvant SWOG S0809 trial was 54% for extrahepatic cholangiocarcinoma, which is quite higher than that shown in the STAMP trial, while 2-year OS rates seem similar.14 The toxicity profile was as expected with these treatments and did not impact negatively on the quality of life. It is, however, worth highlighting the fact that despite a high rate of dose modifications occurring in 92% and 82% of patients in the CisGem and the capecitabine arm, respectively, the rate of patients completing the 8 planned cycles of treatment was high (78% for CisGem and 80% for capecitabine arms). This was much higher than for the BILCAP study (only 55% of patients completed the planned treatment). In addition, treatment interruption due to toxicity in the STAMP trial was lower (3/50 (6%) with CisGem) and 5/50 (10%) with capecitabine) than that in BILCAP (32% in the capecitabine arm). This could be explained by better management of toxicity (investigators had more experience with adjuvant capecitabine at the time of the STAMP trial being performed) and a higher incentive to continue on treatment in the STAMP trial (patients already knew that adjuvant therapy was of benefit) than in BILCAP (at the time of the study being performed, no evidence was available supporting adjuvant treatment and observation was the standard of care at the time). The lower interruption rate for CisGem over capecitabine in the STAMP trial could be explained by similar arguments and the open-label design. Capecitabine remains the standard of care for resected BTC. Unfortunately, the relapse rate remains high, and better treatment options are urgently needed. Whether the combination of CisGem will be the answer may seem unlikely based on the STAMP trial results, but we probably should wait for the ACTICCA-1 study before making a final statement in this regard. The main arguments for this are the fact that ACTICCA-1 is a larger (more than 400 patients) and international study, targeting a wider population of patients (all cholangiocarcinoma and gallbladder cancer). Unanswered questions in the adjuvant setting for BTC are the role of targeted therapies and immunotherapy as adjuvant strategies, since these 2 strategies are already incorporated in the treatment algorithms for advanced settings3 but their role in the adjuvant scenario are not known. International collaboration in the delivery of adequately-powered and well-designed clinical trials in the adjuvant setting in BTC will be the key to exit this maze. We will for sure succeed, we must just “keep going.”